The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer.

BACKGROUND: BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in high-grade serous ovarian cancer, we sought to evaluate the utility of BRCA1 immunohistochemistry (IHC) in screening for BRCA1 loss by germline, somatic, and epigenetic mechanisms. PATIENTS AND METHODS: Patients with advanced high-grade serous ovarian cancer who had previously undergone germline BRCA1 testing were identified. Samples from each tumor were stained for BRCA1 and reviewed independently by two pathologists blinded to BRCA status. Tumors with abnormal BRCA1 IHC and wild-type germline testing underwent further evaluation for somatic BRCA1 mutations and promoter hypermethylation. McNemar's test was used to determine the association of BRCA1 IHC with germline BRCA1 mutations and BRCA1 loss through any mechanism. Kaplan-Meier methods were used to estimate overall survival (OS), and the log-rank test was used to assess differences between groups. RESULTS: Inter-rater reliability between the two pathologists on BRCA IHC interpretation was very good (kappa coefficient 0.865, P = 0.16; McNemar's test). BRCA1 IHC was abnormal in 36% (48/135) of cases. When compared with germline BRCA1 status, BRCA1 IHC had a high negative predictive value (95.4%) but a low positive predictive value (PPV, 52.1%). When accounting for promoter hypermethylation and somatic mutations as alternative methods of BRCA1 loss, the PPV rose to 87.5%. Five-year OS rate was 49.6% [95% confidence interval (CI) 26.3% to 69.3%] for patients with germline BRCA1 mutations, 50.4% (95% CI 27.5% to 69.5%) for germline wild-type BRCA1 and abnormal IHC, and 52.1% (95% CI 38.4% to 64.2%) for germline wild-type BRCA1 and normal IHC (P = 0.92). CONCLUSIONS: BRCA1 IHC interpretation was a highly reproducible and accurate modality for detecting germline, somatic, or epigenetic mechanisms of BRCA1 loss. These results support further development of BRCA1 IHC as a potential biomarker for BRCA1 loss in high-grade serous ovarian cancer.

Optimal (≤1 cm) but visible residual disease: is extensive debulking warranted?

OBJECTIVES: To determine if extensive upper abdominal surgery (UAS) affected overall survival (OS) in patients left with ≤ 1 cm but visible residual disease after undergoing primary cytoreductive surgery for ovarian cancer. Our secondary objective was to determine if leaving ≤ 1cm but visible residual throughout the small bowel (SB) conferred a worse prognosis. METHODS: All stage IIIB-IV ovarian cancer patients who had visible but ≤ 1 cm residual disease at time of primary cytoreductive surgery from 2001 to 2010 were identified. Extensive UAS procedures and residual SB involvement were recorded. RESULTS: The 219 patients identified with ≤1 cm but visible residual disease had a median OS of 51 months. In this cohort, 127 had extensive UAS performed, and 87 had residual disease involving the SB. Univariate OS analysis was performed. There was no significant difference in OS between patients who did or did not have extensive UAS (45 vs. 52 months, P=0.56), or between patients with or without residual SB disease (45 vs. 51 months, P=0.84). Factors that were significantly associated with OS were age, ASA score, family history, and stage. CONCLUSIONS: Patients cytoreduced to ≤ 1 cm but visible residual disease who required UAS did not have a worse OS than those who did not require UAS. OS was similar if residual disease involved the SB or not. For ovarian cancer patients with disease not amenable to complete gross resection, extensive surgery should still be considered to achieve ≤ 1 cm but visible residual disease status, including cases where the residual disease involves the SB.

Clinicopathologic significance of DNA mismatch repair protein defects and endometrial cancer in women 40years of age and younger.

BACKGROUND: The hereditary basis of endometrial cancer is apparent in young women with endometrial cancer. The objective of this study was to examine risk factors and outcomes in patients 40 years of age and younger with endometrial cancer. METHODS: We performed a retrospective cohort study of patients aged 40 years or less who were diagnosed with endometrial carcinoma between 1/93 and 5/08. Clinical and pathologic data were extracted from medical records. Paraffin-embedded slides from hysterectomy specimens were obtained and DNA mismatch repair (MMR) immunohistochemistry was performed. Cases were analyzed according to the presence of DNA MMR protein defects. Standard two-sided statistical tests were performed. RESULTS: Of the 56 identified patients, the median age was 36 years (range, 24-40). The majority of the endometrial carcinomas were of endometrioid histology (91%), stage I (71%), and FIGO grade 1 (59%). Abnormal DNA MMR was found in 9 cases (16%). Cases with abnormal DNA MMR had lower body mass index (BMI) (P=0.05), and had a family history suggestive of Lynch syndrome (P=0.001). Tumors were more likely to have advanced stage disease (P<0.001), be high grade (P<0.001), have deep myometrial invasion (P<0.001), and have lymphovascular invasion (P=0.002). Cases with abnormal DNA MMR had significantly worse overall survival (P=0.028) and progression-free survival (P=0.042). CONCLUSIONS: Endometrial cancer is rare in women aged 40 years or less. In this group of patients, loss of DNA MMR was associated with lower BMI, worse clinicopathologic factors, and worse outcome. These results may have implications when young women diagnosed with endometrial cancer are counseled regarding prognosis.

Sentinel lymph node mapping for endometrial cancer improves the detection of metastatic disease to regional lymph nodes.

OBJECTIVE: To compare the incidence of metastatic cancer cells in sentinel lymph nodes (SLN) vs. non-sentinel nodes in patients who had lymphatic mapping for endometrial cancer and to determine the contribution of metastases detected on ultrastaging to the overall nodal metastasis rate. METHODS: All patients who underwent lymphatic mapping for endometrial cancer were reviewed. Cervical injection of blue dye was used in all cases. Sentinel nodes were examined by routine hematoxylin and eosin (H&E), and if negative, by standardized institutional pathology protocol that included additional sections and immunohistochemistry (IHC). RESULTS: Between 09/2005 and 03/2010, 266 patients with endometrial cancer underwent lymphatic mapping. Sentinel node identification was successful in 223 (84%) cases. Positive nodes were diagnosed in 32/266 (12%) patients. Of those, 8/266 patients (3%) had the metastasis detected only by additional section or IHC as part of SLN ultrastaging. Excluding the 8 cases with positive SLN on ultrastaging only, 24/801 (2.99%) SLN and 30/2698 (1.11%) non-SLN were positive for metastatic disease (p=0.0003). CONCLUSION: Using a cervical injection for mapping, metastatic cells from endometrial cancer are three times as likely to be detected in SLN than in the non-sentinel nodes. This finding strongly supports the concept of lymphatic mapping in endometrial cancer to fine tune the nodal dissection topography. By adding SLN mapping to our current surgical staging procedures we may increase the likelihood of detecting metastatic cancer cells in regional lymph nodes. An additional benefit of incorporating pathologic ultrastaging of SLN is the detection of micrometastasis, which may be the only evidence of extrauterine spread.

Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome.

Founder mutations are an important cause of Lynch syndrome and facilitate genetic testing in specific ethnic populations. Two putative founder mutations in MSH6 were analyzed in 2685 colorectal cancer (CRC) cases, 337 endometrial cancer (EnCa) cases and 3310 healthy controls of Ashkenazi Jewish (AJ) descent from population-based and hospital-based case­control studies in Israel, Canada and the United States. The carriers were haplotyped and the age of the mutations was estimated. MSH6*c.3984_3987dupGTCA was found in 8/2685 CRC cases, 2/337 EnCa cases, and 1/3310 controls, consistent with a high risk of CRC (odds ratio (OR) = 9.9, 95% confidence interval (CI) = 1.2­78.9, p = 0.0079) and a very high risk of EnCa (OR = 19.6, 95% CI = 1.8­217.2, p = 0.0006). MSH6*c.3959_3962delCAAG was identified in 3/2685 CRC cases, 2/337 EnCa cases and no controls. Each mutation was observed on separate conserved haplotypes. MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG probably arose around 585 CE and 685 CE, respectively. No carriers were identified in Sephardi Jews (450 cases and 490 controls). Truncating mutations MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG cause Lynch syndrome and are founder mutations in Ashkenazi Jews. Together with other AJ founder mutations, they contribute substantially to the incidence of CRC and EnCa and are important tools for the early diagnosis and appropriate management of AJ Lynch syndrome patients.

A nomogram for predicting overall survival of women with endometrial cancer following primary therapy: toward improving individualized cancer care.

OBJECTIVES: Traditionally we have relied mainly on final FIGO stage to estimate overall oncologic outcome in endometrial cancer patients. However, it is well known that other patient factors may play equally important roles in outcome. Our objective was to develop a clinically useful nomogram in the hope of providing a more individualized and accurate estimation of overall survival (OS) following primary therapy. METHODS: Using a prospectively maintained endometrial cancer database, 1735 patients treated between 1993 and 2008 were analyzed. Characteristics known to predict OS were collected. For each patient, points were assigned to each of these 5 variables. A total score was calculated. The association between each predictor and the outcome was assessed by multivariable modeling. The corresponding 3-year OS probabilities were then determined from the nomogram. RESULTS: The median age was 62 years (range, 25-96). Final grade included: G1 (471), G2 (622), G3 (634), and missing (8). Stage included: IA (501), IB (590), IC (141), IIA (36), IIB (75), IIIA (116), IIIB (6), IIIC (135), IVA (7), and IVB (128). Histology included: adenocarcinoma (1376), carcinosarcoma (100), clear cell (62), and serous (197). Median follow-up for survivors was 29.2 months (0-162.2 months). Concordance probability estimator for the nomogram is 0.746+/-0.011. CONCLUSION: We developed a nomogram based on 5 easily available clinical characteristics to predict OS with a high concordance probability. This nomogram incorporates other individualized patient variables beyond FIGO stage to more accurately predict outcome. This new tool may be useful to clinicians in assessing patient risk when deciding on follow-up strategies.

The incidence of pelvic lymph node metastasis by FIGO staging for patients with adequately surgically staged endometrial adenocarcinoma of endometrioid histology.

The seminal Gynecologic Oncology Group study on surgical pathologic spread patterns of endometrial cancer demonstrated the risk of pelvic lymph node metastasis for clinical stage I endometrial cancer based on tumor grade and thirds of myometrial invasion. However, the FIGO staging system assigns surgical stage by categorizing depth of myometrial invasion in halves. The objective of this study was to determine the incidence of pelvic lymph node metastasis in endometrial cancer based on tumor grade and myometrial invasion as per the current FIGO staging system. We reviewed the records of all patients who underwent primary surgical staging for clinical stage I endometrial cancer at our institution between May 1993 and November 2005. To make the study cohort as homogeneous as possible, we included only cases of endometrioid histology. We also included only patients who had adequate staging, which was defined as a total hysterectomy with removal of at least eight pelvic lymph nodes. During the study period, 1036 patients underwent primary surgery for endometrial cancer. The study cohort was composed of the 349 patients who met study inclusion criteria. Distribution of tumor grade was as follows: grade 1, 80 (23%); grade 2, 182 (52%); and grade 3, 87 (25%). Overall, 30 patients (9%) had pelvic lymph node metastasis. The incidence of pelvic lymph node metastasis in relation to tumor grade and depth of myometrial invasion (none, inner half, and outer half) was as follows: grade 1-0%, 0%, and 0%, respectively; grade 2-4%, 10%, and 17%, respectively; and grade 3-0%, 7%, and 28%, respectively. We determined the incidence of pelvic nodal metastasis in a large cohort of endometrial cancer patients of uniform histologic subtype in relation to tumor grade and a one-half myometrial invasion cutoff. These data are more applicable to current surgical practice than the previously described one-third myometrial invasion cutoff results.

What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)?

OBJECTIVE: Recent studies have suggested that the definition of optimal cytoreduction for advanced EOC should be changed from the current Gynecologic Oncology Group threshold of < or =1 cm residual disease to no gross residual disease owing to improved survival of patients (pts) rendered macroscopically disease-free. The objective of this study was to analyze survival rates at very specific residual disease diameters to determine the optimal goal of primary cytoreduction for bulky stage IIIC EOC. METHODS: A prospectively kept database was used to identify and review the records of all pts with Stage IIIC EOC who underwent primary cytoreductive surgery at our institution between January 1989 and December 2003. To analyze a homogeneous cohort of cases, we excluded pts with stage IIIC disease based on nodal metastasis alone (without bulky abdominal tumor), fallopian tube or primary peritoneal carcinomas, and borderline tumors. Standard statistical analyses were utilized. RESULTS: The study cohort included 465 pts. The median age was 60 years (range, 25-87), and the median follow-up was 38 months (range, 1-199). Univariate and multivariate analyses, which included various prognostic factors, identified amount of residual disease as a significant prognostic factor (P < 0.001). Median overall survival in relation to the 5 residual disease categories was: no gross residual, 106 months; gross < or =0.5 cm, 66 months; 0.6-1.0 cm, 48 months; 1-2 cm, 33 months; >2 cm, 34 months. Statistical comparison between the 5 residual disease categories revealed 3 distinct groups with significantly different survival rates (P < 0.01). These 3 groups were: (1) no gross residual; (2) gross < or =1 cm residual; and (3) >1 cm residual. Although the difference in survival did not reach statistical significance, within the gross < or =1 cm residual group, there was a trend toward improved survival in pts left with smaller volume, < or =0.5 cm residual compared with those with 0.6-1.0 cm residual (P = 0.06). CONCLUSION: Our data suggest that removal of all evidence of macroscopic disease is associated with prolonged survival and should be the goal of primary cytoreductive surgery. If complete gross resection is not feasible, however, cytoreduction to as minimal residual tumor as possible should be the focus of cytoreductive efforts, as each incremental decrease in residual disease below 1 cm may be associated with an incremental improvement in overall survival.

Risk of endometrial carcinoma associated with BRCA mutation.

OBJECTIVE: Inherited mutations in the BRCA1 or BRCA2 genes are associated with a greatly increased lifetime risk of breast and ovarian cancers and a modestly increased risk of several other cancer types. Several case reports of endometrial carcinoma in women with a BRCA mutation have led to speculation regarding the effect of these genes on the risk of endometrial cancer. The purpose of this study was to test the hypothesis that germline mutation of a BRCA gene is associated with an increased risk of endometrial carcinoma. METHODS: A retrospective cohort of 199 consecutive Ashkenazi Jewish patients with endometrial carcinoma was identified from a 12-year period at this institution. All were genotyped for the three BRCA founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2) that exist in this population, and the case frequency was compared to the known population frequency of these mutations. Additionally, endometrial carcinomas occurring in patients with BRCA mutations were assessed for somatic loss of the wild-type BRCA allele. RESULTS: Germline BRCA mutations were identified in 3 (1 in BRCA1 and two in BRCA2) of 199 (1.5%) patients, compared to a frequency of 2.0% in this population generally. A relative risk of endometrial carcinoma associated with BRCA mutation, as estimated by the odds ratio, was calculated as 0.75 (95% CI = 0.24--2.34; P = 0.6). Loss of the wild-type BRCA allele was observed in two of three tumors associated with a BRCA mutation. CONCLUSIONS: For individuals with a germline BRCA mutation, the lifetime risk of endometrial carcinoma is not increased.

The androgen receptor and genetic susceptibility to ovarian cancer: results from a case series.

Our objectives were to test whether polymorphic variation in the (CAG)n repeat of the androgen receptor (AR) gene affects penetrance of germ-line BRCA mutations for ovarian cancer or age of diagnosis for ovarian cancer. Using a case-series study design, 179 consecutive Ashkenazi Jewish ovarian cancer patients were genotyped for AR repeat length and BRCA mutation status. There was no association between AR repeat length and presence of a BRCA mutation. However, ovarian cancer patients from both groups (with or without BRCA mutation) who carried a short AR allele were diagnosed an average of 7.2 (95% confidence interval, 2.3-12.1) years earlier than patients who did not carry a short allele (P = 0.004). These data suggest that AR allele length affects age of diagnosis of ovarian cancer, irrespective of BRCA mutation status.

Laparoscopic management of adnexal masses in premenopausal and postmenopausal women.

OBJECTIVE: To evaluate the feasibility and safety of laparoscopic adnexal mass removal in patients without preselection for benign pathology and assess the operative complications and findings. METHODS: All patients presenting to the gynecologic oncology service between April 1992 and April 1996 with adnexal masses were candidates for laparoscopic management. Patients underwent preoperative radiological studies and office pelvic examination. Laparoscopic management was attempted on patients without evidence of gross metastatic disease or masses that extended above the umbilicus. Laparotomy was performed if indicated by pathologic findings or technical difficulty. All removed adnexal masses were sent for immediate pathologic diagnosis. The type of procedure, intraoperative findings, and complications were all recorded at the time of procedure. RESULTS: One hundred sixty patients underwent laparoscopic evaluation for an adnexal mass. Benign pathology was discovered in 139 (87%, 95% confidence interval [CI] 84, 90) patients, and 141 (88%, 95% CI 86, 91) patients were managed laparoscopically. Reasons for laparotomy included technical difficulty, operative complications, or malignancy. Frozen section diagnosis was concordant with the final pathology reports in all but five patients (97% concordance), and no discrepancies resulted in treatment delays. CONCLUSION: Laparoscopic management of adnexal masses can be successful in a gynecologic oncology population if there is expertise in operative laparoscopy, availability of immediate accurate pathologic examination, and appropriate further treatment where indicated.

Visual anomia: a unidirectional disconnection.

A right-handed patient with a complete right homonymous hemianopia could not name objects seen in her left hemifield but could always select an object from an assortment when the object was named. If the right hemisphere was devoid of auditory language function, we must postulate separate transcallosal pathways from visual to verbal and from auditory language to visual information. Because only the former pathway was interrupted, our patient exhibited a "unidirectional" disconnection.